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829 results for “Drug resistance”
Data from: The impact of within-host ecology on the fitness of a drug-resistant parasite
Background and objectives: The rate of evolution of drug resistance depends on the fitness of resistant pathogens. The fitness of resistant pathogens is reduced by competition with sensitive pathogens in untreated hosts and so enhanced by competitive release in drug-treated hosts. We set out to estimate the magnitude of those effects on a variety of fitness measures, hypothesizing that competitive suppression and competitive release would have larger impacts when resistance was rarer to begin with. Methodology: We infected mice with varying densities of drug-resistant Plasmodium chabaudi malaria parasites in a fixed density of drug-sensitive parasites and followed infection dynamics using strain-specific quantitative PCR. Results: Competition with susceptible parasites reduced the absolute fitness of resistant parasites by 50-100%. Drug treatment increased the absolute fitness from 2- to >10 000-fold. The ecological context and choice of fitness measure was responsible for the wide variation in those estimates. Initial population growth rates poorly predicted parasite abundance and transmission probabilities. Conclusions and implications: (i) The sensitivity of estimates of pathogen fitness to ecological context and choice of fitness measure make it difficult to derive field-relevant estimates of the fitness costs and benefits of resistance from experimental settings. (ii) Competitive suppression can be a key force preventing resistance from emerging when it is rare, as it is when it first arises. (iii) Drug treatment profoundly affects the fitness of resistance. Resistance evolution could be slowed by developing drug use policies that consider in-host competition.
Data from: Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance
Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing.
Data from: The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection
Malaria infections normally consist of more than one clonally-replicating lineage. Within-host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using the Plasmodium chabaudi mouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co-infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and marked competitive release following treatment. The magnitude of competitive suppression depended on competitor identity. However, there was no overall effect of the diversity of susceptible parasites on the extent of competitive suppression or release. If these findings generalize, then transmission intensity will impact on resistance evolution because of its effect on the frequency of mixed infections, not because of its effect on the distribution of clones per host. This would greatly simplify the computational problems of adequately capturing within-host ecology in models of drug resistance evolution in malaria.
Data from: Plasmids and evolutionary rescue by drug resistance
Antibiotic resistance provides evolutionary rescue for bacterial populations under the threat of extinction through antibiotics. It can arise de novo through mutation in the population, or be obtained from other bacterial populations via the transfer of a resistance-conferring plasmid. We use stochastic modelling methods to establish whether the most likely source of rescue is via a plasmid or via the chromosome, and show that contrary to what is assumed plasmids are not necessarily beneficial locations for resistance genes. Competition at the plasmid level of selection is of great importance - the spread of a resistant plasmid in the population can be slowed or entirely stopped by a non-resistant version of the same plasmid. We suggest that future studies on antibiotic-resistant plasmids should explicitly consider competition at this level of selection.
Data from: Exposure to phages has little impact on the evolution of bacterial antibiotic resistance on drug concentration gradients
The use of phages for treating bacterial pathogens has recently been advocated as an alternative to antibiotic therapy. Here we test a hypothesis that bacteria treated with phages may show more limited evolution of antibiotic resistance as the fitness costs of resistance to phages may add to those of antibiotic resistance, further reducing the growth performance of antibiotic-resistant bacteria. We did this by studying the evolution of phage-exposed and phage-free Pseudomonas fluorescens cultures on concentration gradients of single drugs, including cefotaxime, chloramphenicol, and kanamycin. During drug treatment, the level of bacterial antibiotic resistance increased through time, and was not affected by the phage treatment. Exposure to phages did not cause slower growth in antibiotic-resistant bacteria, although it did so in antibiotic-susceptible bacteria. We observed significant reversion of antibiotic resistance after drug use being terminated, and the rate of reversion was not affected by the phage treatment. The results suggest that the fitness costs caused by resistance to phages are unlikely to be an important constraint on the evolution of bacterial antibiotic resistance in heterogeneous drug environments. Further studies are needed for the interaction of fitness costs of antibiotic resistance with other factors.
Data from: Resource limitation prevents the emergence of drug resistance by intensifying within-host competition
Slowing the evolution of antimicrobial resistance is essential if we are to continue to successfully treat infectious diseases. Whether a drug-resistant mutant grows to high densities, and so sickens the patient and spreads to new hosts, is determined by the competitive interactions it has with drug-susceptible pathogens within the host. Competitive interactions thus represent a good target for resistance management strategies. Using an in vivo model of malaria infection, we show that limiting a resource that is disproportionately required by resistant parasites retards the evolution of drug resistance by intensifying competitive interactions between susceptible and resistant parasites. Resource limitation prevented resistance emergence regardless of whether resistant mutants arose de novo or were experimentally added before drug treatment. Our work provides proof of principle that chemotherapy paired with an "ecological" intervention can slow the evolution of resistance to antimicrobial drugs, even when resistant pathogens are present at high frequencies. It also suggests that a broad range of previously untapped compounds could be used for treating infectious diseases.
Modulation of Multidrug Resistance Protein 1-mediated transport processes by the antiretroviral drug ritonavir
<p>We here provide the structure files, trajectories and topology files for analyzing and reproducing simulations performed in the publication: "<strong>Modulation of Multidrug Resistance Protein 1-mediated transport processes by the antiretroviral drug ritonavir</strong>".</p> <p>Classical molecular dynamics simulation of rat Mrp1 have been performed in complex with native substrates like GSH and GSSG or drug molecules like ritonavir, to study binding modes of different combinations. </p> <p>Structure and trajectory files (all 1 µs long) as well as recorded movies of the time progression are provided for the following simulation systems:</p> <p>1. GSH bound to rat Mrp1</p> <p>2. GSSG bound to rat Mrp1</p> <p>3. Ritonavir bound to rat Mrp1</p> <p>4. GSH + Ritonavir bound to rat Mrp1</p> <p>5. GSSG + Ritonavir bound to rat Mrp1</p> <p>Additionally itp files (GROMACS format) containing parameter information about the ligands GSH, GSSG and Ritonavir are provided for the force field CHARMM36m. </p> <p>Raw data of the homology modeling of rat Mrp1 by I-Tasser as well as Docking results produced via AutoDock4 are uploaded as zip directories. </p> <p> </p>
Data from: Quantification of sensitivity and resistance of breast cancer cell lines to anti-cancer drugs using GR metrics
Traditional means for scoring the effects of anti-cancer drugs on the growth and survival of cell lines is based on relative cell number in drug-treated and control samples and is seriously confounded by unequal division rates arising from natural biological variation and differences in culture conditions. This problem can be overcome by computing drug sensitivity on a per-division basis. The normalized growth rate inhibition (GR) approach yields per-division metrics for drug potency (GR50) and efficacy (GRmax) that are analogous to the more familiar IC50 and Emax values. In this work, we report GR-based, proliferation-corrected, drug sensitivity metrics for ~4,700 pairs of breast cancer cell lines and perturbagens. Such data are broadly useful in understanding the molecular basis of therapeutic response and resistance. Here, we use them to investigate the relationship between different measures of drug sensitivity and conclude that drug potency and efficacy exhibit high variation that is only weakly correlated. To facilitate further use of these data, computed GR curves and metrics can be browsed interactively at http://www.GRbrowser.org/.
Data from: Generalized polyspike train: an EEG biomarker of drug-resistant idiopathic generalized epilepsy
Objective: To identify clinical and EEG biomarkers of drug resistance in adults with idiopathic generalized epilepsy. Methods: We conducted a case-control study consisting of a discovery cohort and a replication cohort independently assessed at two different centres. In each centre patients with idiopathic generalized epilepsy phenotype and generalized spike-wave discharges on EEG were classified as drug-resistant or drug-responsive. EEG changes were classified into pre-defined patterns and compared between the two groups in the discovery cohort. Factors associated with drug resistance in multivariable analysis were tested in the replication cohort. Results: The discovery cohort included 85 patients (29% drug-resistant and 71% drug-responsive). Their median age at assessment was 32 years and 50.6% were female. Multivariable analysis showed that having higher number of seizure types (3 vs. 1: odds ratio [OR]= 31.1, 95% confidence interval [CI] 4.5-214, p<0.001; 3 vs. 2: OR=14.6, 95% CI: 2.3-93.1, p=0.004) and generalized polyspike train (burst of generalized rhythmic spikes lasting less than 1 second) during sleep were associated with drug resistance (OR=10.8, 95% CI: 2.4-49.4, p=0.002). When these factors were tested in the replication cohort of 80 patients (27.5% drug-resistant and 72.5% drug-responsive; 71.3% female; median age 27.5 years), the proportion of patients with generalized polyspike train during sleep was also higher in the drug-resistant group (OR=4.0, 95% CI: 1.35-11.8, p=0.012). Conclusion: Generalized polyspike train during sleep may be an EEG biomarker for drug resistance in adults with idiopathic generalized epilepsy.
The cost effectiveness of surgery for drug resistant temporal lobe epilepsy in the US
<p><strong>Objective:</strong> Surgery is an effective but costly treatment for many patients with drug resistant temporal lobe epilepsy (DR-TLE). We aim to evaluate whether, in the United States, 1) surgery is cost-effective compared to medical management for patients deemed surgical candidates, 2) surgical evaluation is cost-effective for DR-TLE patients in general.</p> <p><strong>Methods:</strong> We use a semi-Markov model to assess the cost-effectiveness of surgery and surgical evaluation over a lifetime horizon. We use 2<sup>nd</sup> order Monte Carlo simulations to conduct probabilistic sensitivity analyses to estimate variation in model output. We adopt both healthcare and societal perspectives, including direct healthcare costs (e.g. surgery, AEDs) and indirect costs (e.g. lost earnings by patients and care providers.) We compare incremental cost-effectiveness ratio (ICER) to societal willingness-to-pay (~$100,000 per Quality Adjusted Life Year) to determine whether surgery is cost-effective.</p> <p><strong>Results:</strong> Epilepsy surgery is cost effective compared to medical management in surgically eligible patients by virtue of being cost saving ($328K vs. 423K) and more effective (16.6 QALY vs. 13.6 QALY) than medical management in the long run. Surgical evaluation is cost-effective in DR-TLE patients even if the probability of being deemed a surgical candidate is only 5%. From a societal perspective, surgery becomes cost effective within 3 years and 89% of simulations favor surgery over the lifetime horizon.</p> <p><strong>Conclusion:</strong> For surgically eligible DR-TLE patients, surgery is cost-effective. For DR-TLE patients in general, referral for surgical evaluation (and possible subsequent surgery) is cost-effective. DR-TLE patients should be referred for surgical evaluation without hesitation on cost-effectiveness grounds.</p>
The incidence and prevalence of drug resistant epilepsy: a systematic review and meta-analysis
<p><strong>Objective:</strong> In order to evaluate the incidence and prevalence of drug-resistant epilepsy (DRE) as well as its predictors and correlates, we conducted a systematic review and meta-analysis of observational studies.</p> <p><strong>Methods: </strong>Our protocol was registered with PROSPERO and the PRISMA and MOOSE reporting standards were followed. We searched MEDLINE, Embase, and Web of Science. We used a double arcsine transformation and random-effects models to carry out our meta-analyses. We performed random-effects meta-regressions using study-level data.</p> <p><strong>Results:</strong> Our search strategy identified 10,794 abstracts. Of these, 103 articles met our eligibility criteria. There was high inter-study heterogeneity and risk of bias. The cumulative incidence of DRE was 25.0 % (95% CI: 16.8, 34.3) in child studies but 14.6% (95% CI: 8.8, 21.6) in adult/mixed ages studies. The prevalence of DRE was 13.7% (95% CI: 9.2, 19.0) in population/community-based populations but 36.3% (95% CI: 30.4, 42.4) in clinic-based cohorts. Meta-regression confirmed that the prevalence of DRE was higher in clinic-based populations and in focal epilepsy. Multiple predictors and correlates of DRE were identified. The most reported of these were having a neurological deficit, an abnormal EEG, and symptomatic epilepsy. The most reported genetic predictors of DRE were polymorphisms of the ABCB1 gene.</p> <p><strong>Conclusions:</strong> Our observations provide a basis for estimating the incidence and prevalence of DRE, which vary between populations. We identified numerous putative DRE predictors and correlates. These findings are important to plan epilepsy services, including epilepsy surgery, a crucial treatment option for people with disabling seizures and DRE.</p>
Protective efficacy of anti-Hyr1p monoclonal antibody against systemic candidiasis due to multi-drug resistant Candida auris
<p>Supplementary data set </p>
Intracellular Metabolic Profiling of Drug Resistant Cells by Surface Enhanced Raman Scattering
<p>SERS spectra of different cell lysates and pure metabolites enhanced by Ag NPs.</p>
The Effect of Probiotic Supplementation in Drug-resistant Epilepsy Patients
ClinicalTrials.gov study NCT03403907. IPD Sharing: NO. Countries: 0. Publications: 3.
A Trial to Evaluate the Male Reproductive Safety of Pretomanid in Adult Male Participants With Drug Resistant Pulmonary Tuberculosis
ClinicalTrials.gov study NCT04179500. IPD Sharing: Not stated. Countries: 2. Publications: 0.
T-20 With Anti-HIV Combination Therapy for Patients With Prior Anti-HIV Drug Treatment and/or Drug Resistance to Each of the Three Classes of Approved Anti-HIV Drugs
ClinicalTrials.gov study NCT00008528. IPD Sharing: Not stated. Countries: 2. Publications: 1.
A Two-year Open-label Extension Study of Ganaxolone in Patients With Drug-resistant Partial-onset Seizures
ClinicalTrials.gov study NCT02519439. IPD Sharing: Not stated. Countries: 1. Publications: 0.
A Study of UCB0942 in Adult Patients With Highly Drug-resistant Focal Epilepsy
ClinicalTrials.gov study NCT02495844. IPD Sharing: Not stated. Countries: 6. Publications: 0.
Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance Following Initiation of TLD
ClinicalTrials.gov study NCT04050449. IPD Sharing: YES. Countries: 6. Publications: 0.
Testing the Sequential Combination of the Anti-cancer Drugs Olaparib Followed by Adavosertib (AZD1775) in Patients With Advanced Solid Tumors With Selected Mutations and PARP Resistance, STAR Study
ClinicalTrials.gov study NCT04197713. IPD Sharing: YES. Countries: 1. Publications: 0.
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These curated guides explain access requirements, typical timelines, costs, and reuse considerations for widely used research datasets.
Allen Brain Atlas
Allen Brain Atlas is an Allen Institute collection of brain map atlases, datasets, APIs, and analysis tools covering mouse, human, and non-human primate brain resources.
Annotated Behaviour and Observability Dataset (ABODe)
ABODe is a University of Edinburgh DataShare dataset for behavior classification in group-housed mice using home-cage video, identities, bounding boxes, ground-plate positions, and annotator labels.
DANDI Archive for NWB datasets
DANDI is a BRAIN Initiative archive for publishing and sharing neurophysiology data, including electrophysiology, optophysiology, and behavioral data packaged as NWB and related standards.
International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.